It would be a glorious thing if we could find a biological cure for diabetes in the next score of years or even if a mechanical device such as the artificial pancreas could be ready for patient use in the foreseeable future. In the meantime, as researchers and engineers struggle to land the big prize, others are working on making exogenous insulin delivery match more closely what happens in normal pathophysiology.
“It would be a significant advancement when we find a way to improve insulin absorption so that it matches the rapid absorption of carbohydrates from the GI tract,” says William Sullivan, M.D., staff endocrinologist at Joslin Diabetes Center.
This is important because the more closely the entry, peak and exit of meal-time insulin correspond to the normal patterns of insulin delivery in the body, the less often episodes of hyperglycemia and hypoglycemia will occur. In theory, not only would this improve safety and blood glucose control, but it would allow patients more freedom with their meals and remove some of the tedious calculations associated with mealplanning.
The insulin composition, delivery method, and local blood perfusion at the insulin delivery site all influence the absorption rate of insulin into the circulation.
The current rapid-acting insulins we have aren’t particularly rapid compared with the body’s own insulin. Meals composed mostly of carbohydrate can send blood glucose levels peaking in 45 minutes to 1 hour post digestion, far ahead of the 90 minute to 2 hour peak associated with the insulin analogs. The result is not enough insulin when you need it and too much accumulated insulin when there isn’t adequate glucose available in the bloodstream. In addition, insulin delivery into the subcutaneous tissue gives rise to a peripheral distribution of insulin, obviating the first pass of insulin through the liver, one of insulin’s primary targets organs. This reduces insulin’s roles in stopping the liver from making and secreting glucose when blood glucose levels are high.
Hence discovering a way to either manufacture faster acting insulin or deliver it more rapidly is a hot topic in biological engineering circles today. There are a number of interesting approaches being taken. A traditional method to approach this has been to fiddle with the amino acid sequence of insulin or make small structural changes in the insulin molecule itself. That is how rapid-acting insulin analogs, (apidra, novolog and Humalog) were developed. Insulin analogs don’t exist in nature, but they resemble the human insulin molecule closely enough to mimic its glucose lowering properties. The Juvenile Diabetes Research Foundation (JDRF) is funding research to develop much more rapid acting insulin that could be used in the artificial pancreas.
Another approach to speeding insulin delivery is to heat the area around the point of injection site. Warmth increases blood flow to the injection site thereby dispersing the insulin faster. Massaging the injection site will stimulate blood flow, but the amount of time necessary to create sufficient warmth to speed insulin delivery and the lack of standardization makes it an unwieldy practice for everyday use. The devices being developed are in the form of a specialized heating pad attached to a controller device. These mechanisms are coupled with insulin pumps. The heating pad component is attached to the tubing on the infusion set and the controller is affixed to the insulin pump. Once the controller senses the initiation of insulin delivery the heating pad is activated.
A third approach being investigated is intradermal microneedle delivery. The dermis is the skin layer under the epidermis directly above the muscle layer. In subcutaneous injections, the insulin injections used today, insulin is deposited into the epidermis. The dermis is well vascularized and injecting into it ensures more rapid delivery of insulin. However, aiming for the dermis with today’s needles can be dangerous and can lead to intramuscular injections. Scientists are developing microneedles that can dissolve in the skin tissue once injected. Even though the microneedles do damage the skin,it is able to repair itself rapidly.
Piggybacking insulin with hyaluronan is another method that is being tested to reduce the time it takes for insulin to reach its target cells. Hyaluronic acid occurs naturally in the body helping keep the joints lubricated. The combination of the two allows insulin to move through the subcutaneous space faster permitting insulin to reach the bloodstream and lower glucose levels faster.
It will be interesting to see which of these designs reach the market first and what impact they have on patients’ everyday care patterns and comfort level.